Equine Protozoal Myeloencephalitis (EPM) is the leading infectious neurologic disease of American horses. Consistently safe and effective treatments for this disease are not available. Conventional therapy relies on relatively non-specific drug/medication combinations; these approaches are only partially effective and relapses and/or adverse reactions are common.
EPM is a New World disease and is the most common infectious neurological disease of horses in the Western hemisphere. It is caused by an "apicomplexan" parasite called Sarcocystis neurona (S. neurona), which cycles naturally between opossums and birds. The horse is an aberrant host, becoming exposed when it consumes infectious material from opossum feces. In the horse, S. neurona makes its way to the brain and spinal cord, where it proliferates and causes clinical disease.
The epidemiology and economic significance of S. neurona infection is substantial. In endemic areas in the U.S., over 40% of horses are seropositive. Of these, a small percentage are clinically affected. Of animals clinically affected, 30-40% reportedly fail to respond to current therapy, and some of these animals die. Better and more effective prophylactic and therapeutic modalities are required.
The economic loss in performance horse breeding is likely more substantial than the above figures suggest. The figures presented refer to clinically observable infections only. Subclinical infections will show only at the racetrack, where well-bred animals may fail to perform to their genetic potential because of subclinical infection with EPM. While unrecorded, these losses may be significant.
EPM occurs wherever opossums are found. All cases of EPM therefore trace to Western hemisphere exposure, and the incidence of EPM is likely greatest in areas with high opossum populations. However, clinical cases of EPM are found throughout the world, because horses who become infected with S. neurona while in opossum territories may be transported elsewhere.
The localization of S. neurona in the brain and spinal cord is a critical obstacle to treatment of EPM. The brain and spinal cord are immunologically privileged; as such, immune responses are likely less effective in the brain than elsewhere. Current treatments, as detailed below, do not directly kill S. neurona; as such they often fail to effect a "cure." The present treatment method directly kills S. neurona, making it dramatically different from previous treatments.
Previous therapy for BPM consists of administration of various combinations of sulfonamides, trimethoprim and pyrimethamine (Daraprim). However, many horses relapse when therapy ceases, probably because the current therapies do not cross the blood/brain barrier reliably and/or attack the organism directly. These agents only hinder proliferation of S. neurona and do not kill it. The inability of current treatments to kill S. neurona likely contributes to the significant relapse rate after therapy ceases.
One of the major concerns about current therapeutic approaches to EPM is the difficulty in maintaining simultaneous minimum inhibitory concentrations (MICs) of pyrimethamine, trimethoprim and sulfonamides in the CNS. Because of the uncertainty of the oral bioavailability and steady state concentrations of these agents in the CNS, and the fact that other treatment regimens may be only apicomplexistatic, the availability of a highly lipid-soluble agent with a long plasma half-life, good CNS entry characteristics, and the ability to kill S. neurona in the CNS would be a useful addition to the anti-EPM therapeutic armamentarium. Additionally, current therapeutic approaches are associated with significant adverse responses in treated animals, one of which is dysbacteriosis resulting in lethal diarrhea and anemia. A more effective and less toxic agent would be highly desirable. The present invention provides these features, whereas the previous treatments do not
The present treatment methods utilize triazine-based anticoccidials, preferably diclazuril, to prevent and treat EPM, without the side effects of previous EPM treatments. EPM and coccidiosis are both caused by "apicomplexan" parasites; however, coccidiosus does not affect the CNS as does EPM.
Triazine-based compounds have previously been used in the prophylaxis of coccidiosis in poultry in Canada, Europe, and South America. Vanparijs et. al., 129 Vet. Rec. 339 (1991); Driessen et. al., 72 Aust. Vet. 139 (1995). Diclazuril has been used to treat coccidiosus in turkeys, ducks, quail, guinea-fowl, pheasants, partridges, mice, rats, dogs, rabbits, cattle, and horses. Lindsay et al., 55 Am. J. Vet. Res. 976 (1994); Lindsay et al., 81(2) J. Parisitol. 315 (1995); and Vanparijs et al., 32 Vet. Parisitol. 109 (1989). U.S. Pat. No. 4,952,570 also discloses the use of triazine-based compounds (including diclazuril) to treat protozoal infections, although neither Equine Protozoal Myelitis nor S. neurona are mentioned. Moreover, diclazuril, in particular is generally considered non-absorbable by the small intestine, and systemic treatment of protozoal infections not possible.
Diclazuril has been shown to be active against Neospora caninum, another apicomplexan organism, in vitro but not yet in vivo. Lindsay et. al., 55 Amer. V et. J. R. 926 (1994) and Dubey and Lindsay, 67 Vet. Parisitol. 1 (1996). Diclazuril has also been shown to be effective against intestinal Eimeria spp. in many avian hosts and against intestinal and hepatic coccidiosis in rabbits. Vanparijs et. al., 32 Vet. Parisitol. 109 (1989).
In other work, diclazuril has been used in the prophylaxis and treatment of experimental T. gondii infection in mice. While diclazuril alone or in combination with pyrimethamine protected mice against death following inoculation with T. gondii, diclazuril, alone or in combination did not prevent tissue cyst formation, including brain tissue cyst formation in surviving mice. Based on this work in mice, Lindsay concluded that combinations of diclazuril and pyrimethamine may be beneficial in the treatment of toxoplasmosis in man and animals Lindsay et. al., 81(2) J. Parisitol. 315 (1995). More importantly, the mice in these experiments died from pneumonia and hepatitis; there is no evidence from the Lindsay experiments to suggest that diclazuril is effective in the treatment of encephalitis. The data show that diclazuril did not prevent tissue cyst formation in the CNS.